tbuckley/cabot-search huggingface dataset:
Optical Control of Tissue Regeneration through Photostimulation of Organic Semiconducting Nanoparticles
Authors: Giada Onorato, Federica Fardella, Anna Lewinska, Federico Gobbo, Giuseppina Tommasini, Maciej Wnuk, Angela Tino, Maria Moros, Maria Rosa Antognazza, Claudia Tortiglione
Journal: Advanced Healthcare Materials (2022)

Next generation bioengineering strives to identify crucial cues that trigger regeneration of damaged tissues, and to control the cells that execute these programs with biomaterials and devices. Molecular and biophysical mechanisms driving embryogenesis may inspire novel tools to reactivate developmental programs in situ. Here nanoparticles based on conjugated polymers are employed for optical control of regenerating tissues by using an animal with unlimited regenerative potential, the polyp Hydra, as in vivo model, and human keratinocytes as an in vitro model to investigate skin repair. By integrating animal, cellular, molecular, and biochemical approaches, nanoparticles based on poly-3-hexylthiophene (P3HT) are shown able to enhance regeneration kinetics, stem cell proliferation, and biomolecule oxidation levels. Opposite outputs are obtained with PCPDTBT-NPs (Poly[2,6-(4,4-bis-(2-ethylhexyl)-4H-cyclopenta [2,1-b;3,4-b'] dithiophene)-alt-4,7(2,1,3-benzothiadiazole)], causing a beneficial effect on Hydra regeneration but not on the migratory capability of keratinocytes. These results suggest that the artificial modulation of the redox potential in injured tissues may represent a powerful modality to control their regenerative potential. Importantly, the possibility to fine-tuning materials' photocatalytic efficiency may enable a biphasic modulation over a wide dynamic range, which can be exploited to augment the tissue regenerative capacity or inhibit the unlimited potential of cancerous cells in pathological contexts.
The Value of Diagnostic Imaging in Stroke—Are We Asking the Right Question?
Authors: Bruce C. V. Campbell
Journal: JAMA Network Open (2022)

many events that may intervene and be a potentially confounding factor in functional outcomes and mortality.Stroke is a clinically complex area, and it is important to consider whether there is a specific clinical question that a test will address before ordering any investigation.In the case of MRI after stroke, it may be to confirm the diagnosis, clarify stroke localization (eg, to confirm likelihood of a stenosis being symptomatic), provide hints of stroke causes, determine timing of anticoagulation, assess the severity of underlying small vessel disease, or assess prognosis.Asking any of these valid clinical questions may help improve clinical care by targeting subsequent therapies most appropriately.However, asking whether the imaging alters mortality may not be the right question.
COLUMBUS 5-Year Update: A Randomized, Open-Label, Phase III Trial of Encorafenib Plus Binimetinib Versus Vemurafenib or Encorafenib in Patients With<i>BRAF</i>V600–Mutant Melanoma
Authors: Reinhard Dummer, Keith T. Flaherty, Caroline Robert, Ana Arance, Jan Willem B. de Groot, Claus Garbe, Helen J. Gogas, Ralf Gutzmer, Ivana Krajsová, Gabriella Liszkay, Carmen Loquai, Mario Mandalà, Dirk Schadendorf, Naoya Yamazaki, Alessandra di Pietro, Jean Cantey-Kiser, Michelle Edwards, Paolo A. Ascierto
Journal: Journal of Clinical Oncology (2022)

Combination treatment with BRAF and MEK inhibitors has demonstrated benefits on progression-free survival (PFS) and overall survival (OS) and is a standard of care for the treatment of advanced BRAF V600-mutant melanoma. Here, we report the 5-year update from the COLUMBUS trial (ClinicalTrials.gov identifier: NCT01909453).Patients with locally advanced unresectable or metastatic BRAF V600-mutant melanoma, untreated or progressed after first-line immunotherapy, were randomly assigned 1:1:1 to encorafenib 450 mg once daily plus binimetinib 45 mg twice daily, vemurafenib 960 mg twice daily, or encorafenib 300 mg once daily. An updated analysis was conducted 65 months after the last patient was randomly assigned.Five hundred seventy-seven patients were randomly assigned: 192 to encorafenib plus binimetinib, 191 to vemurafenib, and 194 to encorafenib. The 5-year PFS and OS rates with encorafenib plus binimetinib were 23% and 35% overall and 31% and 45% in those with normal lactate dehydrogenase levels, respectively. In comparison, the 5-year PFS and OS rates with vemurafenib were 10% and 21% overall and 12% and 28% in those with normal lactate dehydrogenase levels, respectively. The median duration of response with encorafenib plus binimetinib was 18.6 months, with disease control achieved in 92.2% of patients. In comparison, the median duration of response with vemurafenib was 12.3 months, with disease control achieved in 81.2% of patients. Long-term follow-up showed no new safety concerns, and results were consistent with the known tolerability profile of encorafenib plus binimetinib. Interactive visualization of the data presented in this article is available at COLUMBUS dashboard.In this 5-year update of part 1 of the COLUMBUS trial, encorafenib plus binimetinib treatment demonstrated continued long-term benefits and a consistent safety profile in patients with BRAF V600-mutant melanoma.
The biology and inhibition of glucose‐regulated protein 94/gp96
Authors: Kyler W. Pugh, Marim Alnaed, Christopher M. Brackett, Brian S. J. Blagg
Journal: Medicinal Research Reviews (2022)

Abstract The 94 kDa molecular chaperone, glucose‐regulated protein 94 (Grp94), has garnered interest during the last decade due to its direct association with endoplasmic reticulum (ER) stress and disease. Grp94 belongs to the Hsp90 family of molecular chaperones and is a master regulator of ER homeostasis due to its ability to fold and stabilize proteins/receptors, and to chaperone misfolded proteins for degradation. Multiple studies have demonstrated that Grp94 knockdown or inhibition leads to the degradation of client protein substrates, which leads to disruption of disease‐dependent signaling pathways. As a result, small molecule inhibitors of Grp94 have become a promising therapeutic approach to target a variety of disease states. Specifically, Grp94 has proven to be a promising target for cancer, glaucoma, immune‐mediated inflammation, and viral infection. Moreover, Grp94‐peptide complexes have been utilized effectively as adjuvants for vaccines against a variety of disease states. This work highlights the significance of Grp94 biology and the development of therapeutics that target this molecular chaperone in multiple disease states.
International Olympic Committee (IOC) consensus statement on acute respiratory illness in athletes part 1: acute respiratory infections
Authors: Martin Schwellnus, Paolo Emilio Adami, Valerie Bougault, Richard Budgett, Hege Havstad Clemm, Wayne Derman, Uğur Erdener, Ken Fitch, James H Hull, Cameron McIntosh, Tim Meyer, Lars Pedersen, David B Pyne, Tonje Reier-Nilsen, Wolfgang Schobersberger, Yorck Olaf Schumacher, Nicola Sewry, Torbjørn Soligard, Maarit Valtonen, Nick Webborn, Lars Engebretsen
Journal: British Journal of Sports Medicine (2022)

Acute illnesses affecting the respiratory tract are common and form a significant component of the work of Sport and Exercise Medicine (SEM) clinicians. Acute respiratory illness (ARill) can broadly be classified as non-infective ARill and acute respiratory infections (ARinf). The aim of this consensus is to provide the SEM clinician with an overview and practical clinical approach to ARinf in athletes. The International Olympic Committee (IOC) Medical and Scientific Commission appointed an international consensus group to review ARill (non-infective ARill and ARinf) in athletes. Six subgroups of the IOC Consensus group were initially established to review the following key areas of ARill in athletes: (1) epidemiology/risk factors for ARill, (2) ARinf, (3) non-infective ARill including ARill due to environmental exposure, (4) acute asthma and related conditions, (5) effects of ARill on exercise/sports performance, medical complications/return-to-sport and (6) acute nasal/vocal cord dysfunction presenting as ARill. Several systematic and narrative reviews were conducted by IOC consensus subgroups, and these then formed the basis of sections in the consensus documents. Drafting and internal review of sections were allocated to ‘core’ members of the consensus group, and an advanced draft of the consensus document was discussed during a meeting of the main consensus core group in Lausanne, Switzerland on 11 to 12 October 2021. Final edits were completed after the meeting. This consensus document (part 1) focusses on ARinf, which accounts for the majority of ARill in athletes. The first section of this consensus proposes a set of definitions and classifications of ARinf in athletes to standardise future data collection and reporting. The remainder of the consensus paper examines a wide range of clinical considerations related to ARinf in athletes: epidemiology, risk factors, pathology/pathophysiology, clinical presentation and diagnosis, management, prevention, medical considerations, risks of infection during exercise, effects of infection on exercise/sports performance and return-to-sport guidelines.
Prevalence of adverse electrophysiological and audiometric changes in nontuberculous mycobacterium treatment regimens
Authors: Madeline Mellett, Christina S. Thornton, Leila Barss, Rachel K. Lim, Dina A. Fisher, Julie Jarand, Stephen K. Field
Journal: European Respiratory Journal (2022)

<b>QTc prolongation was associated with clofazimine treatment and in two cases resulted in a treatment change. Audiometric deterioration was found but had limited clinical impact. Frequent ECG and audiometry monitoring may be unnecessary in all patients.</b>https://bit.ly/3uI244P
Safety and Adverse Events Among Long-term Care Residents Receiving a Third COVID-19 mRNA Vaccine Booster Dose in Quebec
Authors: Xi Sophie Zhang, Andréanne Moreau, Diana Cruz-Santiago, Stéphanie Langevin, Quoc Dinh Nguyen
Journal: JAMA Network Open (2022)

J. Daniel Kelly, MD, PhD; Samuel Leonard, MS; Katherine J. Hoggatt, PhD; W. John Boscardin, PhD; Emily N. Lum, MPH; Tristan A. Moss-Vazquez, BA; Raul Andino, PhD; Joseph K. Wong, MD; Amy Byers, PhD; Dawn M. Bravata, MD; Phyllis C. Tien, MD; Salomeh Keyhani, MD, MPH
Broadening the MIND: Tafasitamab and Lenalidomide versus Synthetic Controls
Authors: Hua-Jay J. Cherng, Jason R. Westin
Journal: Clinical Cancer Research (2022)

Tafasitamab and lenalidomide were approved for second-line treatment of diffuse large B-cell lymphoma (DLBCL) based on a single-arm phase II study. This combination was superior to routine immunochemotherapy regimens when comparing matched observational cohorts. "Synthetic" control groups may support use of novel DLBCL therapies in the absence of randomized studies. See related article by Nowakowski et al., p. 4003.
Reply
Authors: Laurens A. van Kleef, Milan J. Sonneveld, Robert J. de Knegt
Journal: Hepatology (2022)

We appreciate the interest of Ning et al. in our study demonstrating steatosis not being associated with excess mortality in community‐dwelling elders.1,2 Their main concern is using 8.0 kPa as the cutoff for identifying individuals at high‐risk of fibrosis. This cutoff was based on recommendations outlined in the 2021 EASL guideline on non‐invasive tests.3 However, we performed extensive additional analyses, including liver stiffness as a continuous variable and applying a higher cutoff (10.0 kPa), both of which yielded similar results. Notably, liver stiffness values typically associated with cirrhosis (e.g., more than or equal to 15.0 kPa) are rare among community‐dwelling elderly without heart failure. In fact, in our population, only 0.2% exceeded this threshold. Although, at first glance, this might seem to contrast with results from histology‐proven NAFLD cohorts, it should be noted that such populations do not reflect the general population but represent a selection referred for further evaluation. This distinction is crucial for our conclusions, and results should not be generalized to elderly patients with steatosis and fibrosis, who are already under specialist care. Another potential issue highlighted is the generalizability toward non‐European populations. Our study suggests that steatosis in the last decades of life does not impair life expectancy, probably because of high competing mortality risk of non–liver‐related origin. Given the global differences in (liver‐related) comorbidities and life expectancy, careful external validation of our findings is warranted. It is likely that our cutoff for defining elders may need to be reassessed in other populations and may be subject to change because of the ongoing increase in life expectancy. Additional studies that include other ethnicities and additional age categories should further elucidate this important topic. Furthermore, the authors mentioned potential bias by healthcare interventions after steatosis assessment. Besides no drugs being approved for steatosis, we note that participants in our population‐based cohort were not referred to healthcare professionals in the case of steatosis. Moreover, in the Netherlands (like many countries), there is a strict cardiovascular‐risk management program, comprising treating metabolic health factors typically associated with steatosis. Hence, lifestyle recommendations and pharmaceutical interventions were independent of incidental findings during study visits. Finally, steatosis not increasing mortality risk in the elderly aligns with the peak age of death due to chronic liver disease in Europe, which is the late 40s and early 50s. This contrasts smoking‐related and other obesity‐related mortality, which typically occurs decades later.4 This indicates that elderly individuals with chronic liver disease are likely to be relatively healthy survivors, supporting our hypothesis that screening for fatty liver disease in an elderly community‐dwelling population is unlikely to improve their outcomes.
Preclinical Development of [211At]meta- astatobenzylguanidine ([211At]MABG) as an Alpha Particle Radiopharmaceutical Therapy for Neuroblastoma
Authors: Vandana Batra, Minu Samanta, Mehran Makvandi, David Groff, Paul Martorano, Jimmy Elias, Pietro Ranieri, Matthew Tsang, Catherine Hou, Yimei Li, Bruce Pawel, Daniel Martinez, Ganesan Vaidyanathan, Sean Carlin, Daniel A. Pryma, John M. Maris
Journal: Clinical Cancer Research (2022)

[131I]meta-iodobenzylguanidine ([131I]MIBG) is a targeted radiotherapeutic administered systemically to deliver beta particle radiation in neuroblastoma. However, relapses in the bone marrow are common. [211At]meta-astatobenzylguanidine ([211At] MABG) is an alpha particle emitter with higher biological effectiveness and short path length which effectively sterilizes microscopic residual disease. Here we investigated the safety and antitumor activity [211At]MABG in preclinical models of neuroblastoma.We defined the maximum tolerated dose (MTD), biodistribution, and toxicity of [211At]MABG in immunodeficient mice in comparison with [131I]MIBG. We compared the antitumor efficacy of [211At]MABG with [131I]MIBG in three murine xenograft models. Finally, we explored the efficacy of [211At]MABG after tail vein xenografting designed to model disseminated neuroblastoma.The MTD of [211At]MABG was 66.7 MBq/kg (1.8 mCi/kg) in CB17SC scid-/- mice and 51.8 MBq/kg (1.4 mCi/kg) in NOD.Cg-Prkdcscid Il2rgtm1Wjl/SzJ (NSG) mice. Biodistribution of [211At]MABG was similar to [131I]MIBG. Long-term toxicity studies on mice administered with doses up to 41.5 MBq/kg (1.12 mCi/kg) showed the radiotherapeutic to be well tolerated. Both 66.7 MBq/kg (1.8 mCi/kg) single dose and fractionated dosing 16.6 MBq/kg/fraction (0.45 mCi/kg) × 4 over 11 days induced marked tumor regression in two of the three models studied. Survival was significantly prolonged for mice treated with 12.9 MBq/kg/fraction (0.35 mCi/kg) × 4 doses over 11 days [211At]MABG in the disseminated disease (IMR-05NET/GFP/LUC) model (P = 0.003) suggesting eradication of microscopic disease.[211At]MABG has significant survival advantage in disseminated models of neuroblastoma. An alpha particle emitting radiopharmaceutical may be effective against microscopic disseminated disease, warranting clinical development.
Experimental Verification on Steering Flight of Honeybee by Electrical Stimulation
Authors: Li Yu, Jieliang Zhao, Zhiyun Ma, Wenzhong Wang, Shaoze Yan, Yue Jin, Yu Fang
Journal: Cyborg and Bionic Systems (2022)

The artificial locomotion control strategy is the fundamental technique to ensure the accomplishment of the preset assignments for cyborg insects. The existing research has recognized that the electrical stimulation applied to the optic lobes was an appropriate flight control strategy for small insects represented by honeybee. This control technique has been confirmed to be effective for honeybee flight initiation and cessation. However, its regulation effect on steering locomotion has not been fully verified. Here, we investigated the steering control effect of honeybee by applying electrical stimulation signals with different duty cycles and frequencies on the unilateral optic lobes and screened the stimulus parameters with the highest response successful rate. Moreover, we confirmed the effectiveness of steering control by verifying the presence of rotation torque on tethered honeybees and the body orientation change of crawling honeybees. Our study will contribute some reliable parameter references to the motion control of cyborg honeybees.
Gastric bypass was performed with a novel through-the-scope twin clip under endoscopy
Authors: Qiang Zhang, Zhen Wang, Side Liu
Journal: Endoscopy (2022)

A novel through-the-scope twin clip (TTS-TC) (Micro-Tech Co. Ltd., Nanjing, China) was first reported by us [1] [2]. The TTS-TC is composed of a middle column and two clips on both sides. Here, we initially explored gastric bypass with the TTS-TCs under endoscopy in a live pig.
Hijacking of transcriptional condensates by endogenous retroviruses
Authors: Vahid Asimi, Abhishek Sampath Kumar, Henri Niskanen, Christina Riemenschneider, Sara Hetzel, Julian Naderi, Nina Fasching, Niko Popitsch, Manyu Du, Helene Kretzmer, Zachary D. Smith, Raha Weigert, Maria Walther, Sainath Mamde, David Meierhofer, Lars Wittler, René Buschow, Bernd Timmermann, Ibrahim I. Cisse, Stefan L. Ameres, Alexander Meissner, Denes Hnisz
Journal: Nature Genetics (2022)

Abstract Most endogenous retroviruses (ERVs) in mammals are incapable of retrotransposition; therefore, why ERV derepression is associated with lethality during early development has been a mystery. Here, we report that rapid and selective degradation of the heterochromatin adapter protein TRIM28 triggers dissociation of transcriptional condensates from loci encoding super-enhancer (SE)-driven pluripotency genes and their association with transcribed ERV loci in murine embryonic stem cells. Knockdown of ERV RNAs or forced expression of SE-enriched transcription factors rescued condensate localization at SEs in TRIM28-degraded cells. In a biochemical reconstitution system, ERV RNA facilitated partitioning of RNA polymerase II and the Mediator coactivator into phase-separated droplets. In TRIM28 knockout mouse embryos, single-cell RNA-seq analysis revealed specific depletion of pluripotent lineages. We propose that coding and noncoding nascent RNAs, including those produced by retrotransposons, may facilitate ‘hijacking’ of transcriptional condensates in various developmental and disease contexts.
Acute hepatitis of unknown origin in children: Behind the statistics
Authors: Randa Elsheikh, Hoang Thuy Tien, Abdelrahman M. Makram, Nguyen Thanh Van, Trang Thi Bich Le, Tamilarasy Vasanthakumaran, Nguyen Tien Huy
Journal: Hepatology (2022)

Since April 2022, the world has been witnessing a rapidly spreading outbreak of acute hepatitis of unknown origin in children &lt; 16 years old that has affected several countries around the world. Most of the cases have presented with the clinical picture of severe hepatitis that has led to resorting to liver transplantation in several cases. Despite the numerous theories that have been suggested on the possible underlying etiologies of the outbreak, an association with hepatitis A–E viruses and a link to COVID‐19 vaccines have been excluded. Adenovirus serotype 41 has been detected in numerous cases, which makes it the most likely underlying cause of the disease. Nevertheless, other hypotheses are being investigated to justify the severity of the clinical picture, which is not typical of this type of virus. This review aims to summarize the current knowledge about the outbreak, highlight the suggested working hypotheses, and report the public health measures undertaken to tackle the outbreak.
Uncertainties About the Optimal Timing of Fourth Dose of COVID-19 Vaccines
Authors: Joshua Nealon, Benjamin J. Cowling
Journal: JAMA Network Open (2022)

Noa Eliakim-Raz, MD; Amos Stemmer, MD; Nassem Ghantous, MD; Asaf Ness, MD; Muhammad Awwad, MD; Yaara Leibovici-Weisman, MD; Salomon M. Stemmer, MD
Telephone risk-based eligibility assessment for low-dose CT lung cancer screening
Authors: Jennifer L Dickson, Helen Hall, Carolyn Horst, Sophie Tisi, Priyam Verghese, Anne-Marie Mullin, Jonathan Teague, Laura Farrelly, Vicky Bowyer, Kylie Gyertson, Fanta Bojang, Claire Levermore, Tania Anastasiadis, Karen Sennett, John McCabe, Anand Devaraj, Arjun Nair, Neal Navani, Matthew EJ Callister, Allan Hackshaw, Samantha L Quaife, Sam M Janes
Journal: Thorax (2022)

Eligibility for lung cancer screening (LCS) requires assessment of lung cancer risk, based on smoking history alongside demographic and medical factors. Reliance on individual face-to-face eligibility assessment risks inefficiency and costliness. The SUMMIT Study introduced a telephone-based lung cancer risk assessment to guide invitation to face-to-face LCS eligibility assessment, which significantly increased the proportion of face-to-face attendees eligible for LCS. However, levels of agreement between phone screener and in-person responses were lower in younger individuals and minority ethnic groups. Telephone-based risk assessment is an efficient way to optimise selection for LCS appointments but requires further iteration to ensure an equitable approach.
Isoniazid and rifapentine treatment effectively reduces persistent M. tuberculosis infection in macaque lungs
Authors: Riti Sharan, Shashank R. Ganatra, Dhiraj K. Singh, Journey Cole, Taylor W. Foreman, Rajesh Thippeshappa, Charles A. Peloquin, Vinay Shivanna, Olga Gonzalez, Cheryl L. Day, Neel R. Gandhi, Edward J. Dick, Shannan Hall-Ursone, Smriti Mehra, Larry S. Schlesinger, Jyothi Rengarajan, Deepak Kaushal
Journal: Journal of Clinical Investigation (2022)

A once-weekly oral dose of isoniazid and rifapentine for 3 months (3HP) is recommended by the CDC for treatment of latent tuberculosis infection (LTBI). The aim of this study is to assess 3HP-mediated clearance of M. tuberculosis bacteria in macaques with asymptomatic LTBI. Twelve Indian-origin rhesus macaques were infected with a low dose (~10 CFU) of M. tuberculosis CDC1551 via aerosol. Six animals were treated with 3HP and 6 were left untreated. The animals were imaged via PET/CT at frequent intervals. Upon treatment completion, all animals except 1 were coinfected with SIV to assess reactivation of LTBI to active tuberculosis (ATB). Four of 6 treated macaques showed no evidence of persistent bacilli or extrapulmonary spread until the study end point. PET/CT demonstrated the presence of significantly more granulomas in untreated animals relative to the treated group. The untreated animals harbored persistent bacilli and demonstrated tuberculosis (TB) reactivation following SIV coinfection, while none of the treated animals reactivated to ATB. 3HP treatment effectively reduced persistent infection with M. tuberculosis and prevented reactivation of TB in latently infected macaques.